roger a. fielding, phd director and senior scientist professor of … · director and senior...
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© Tufts University, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging
Roger A. Fielding, PhD Director and Senior Scientist
Professor of Nutrition and Medicine Nutrition, Exercise Physiology, and Sarcopenia Laboratory
Frailty conundrums: dilemmas and unsolved conceptual issues.
WHO: Frailty Network Meeting
Geneva, Switzerland Nov 2016
Disclosures:
• Consultancies: Merck, Eli Lilly, Essentient, Regeneron, Dairy Management Inc., Nestle’ Inc.
• Advisory board memberships: Cytokinetics, Segterra, Aging in Motion, Myosyntax, Ammonett.
• Grant support: NIH (NIA, NHLBI, NIDDK), USDA, Department of Defense, Dairy Research Institute, Unilever, Nestle’ Inc., Regeneron.
Skeletal Muscle Matters!
• Makes up 45-50% of body mass
• Fundamental role in locomotion, O2 consumption, whole-body energy metabolism, and substrate turnover and storage
• Secretory organ (myokines)
• Robust skeletal muscle is a central factor in whole-body health and essential for maintaining energy homeostasis
Rivas & Fielding. Muscle. Encyclopedia of Human Nutrition (3rd Ed.) 2012
Mobility across species
Dickinson et al. Science 2000; 288:5463
Aging drosophila and performance
Miller et al. Biophys J 2008;95:2391
HABC – 400 m walk performance and mortality
Newman et al. JAMA; 2006;295:2018
Sarcopenia: Age-associated loss in muscle mass and function
Female 70 yrs. BMI = 23.3
Female 85 yrs. BMI = 24.6
Sarcopenia is a key biological component of the frailty syndrome
Historic Alignment Worldwide of Societal, Governmental, and Pharmaceutical Industry Interest in Sarcopenia: • Recognized priority area of research by NIA: NIA-PCORI
Initiative STRIDE Study, LIFE Study.
• IMI EU initiative: SPRINT-T Trial.
• Increased international awareness of Sarcopenia: WCO, IFSCR.
• Multiple candidate molecules in early and mid-stage development targeting skeletal muscle dysfunction, sarcopenia, and ultimately frailty.
• October 2016 establishment of ICD-10 for Sarcopenia.
Behavioral Interventions to target
Frailty
FRAILTY
Frailty state of increased vulnerability to stressor events confering high risk for major negative outcomes, including disability, falls, fractures and mortality
Consensus on its operationalization has not yet been achieved
Most widely used definition operationalized by Fried et al. phenotype of frailty, validated in the CHS study, with the presence of ≥3 of 5 criteria denoting frailty
(weight loss, self-reported exhaustion, low energy expenditure, slow gait speed, and weak grip strength)
Clegg et al. Lancet 2013 Keevil et al. Proc Nutr Soc 2015
Fried et al. J Gerontol A Biol Sci Med Sci 2001
FRAILTY AND EXERCISE
Simpler tool validated using data from the SOF study the SOF frailty
index, with the presence of ≥2 criteria of 3 denoting frailty (weight loss, inability to rise from a chair 5 times without using arms, and self-reported reduced energy level)
Predict risk of disability, falls, fracture, and mortality as well as the more complex Fried frailty index
SOF frailty index does not integrate the level of physical activity, making this tool potentially more meaningful for the evaluation of physical activity-based interventions
Ensrud et al. Arch Intern Med 2008
Lifestyle Interventions and Independence for Elders*
• Design: a Phase 3 RCT (LIFE-M)
•N = 1600 (8 clinical centers)
•Mean FU: 2.7 years (min 1.9 - max 3.9
years)
• Intervention: aerobic + resistance
exercise vs. health education
*Fielding et al. J. Gerontol. 2011
• 70-89 years
• Age 70-89 yrs
• Sedentary
• Able to walk 400 m
• SPPB score <9 (45% <7)
Inclusion criteria
Tufts University BYMCU
HR=0.82, 95%CI=0.69-0.98 p=0.03
Physical activity
Health Education
Pahor et al JAMA 2014
Physical activity
(n=818)
Health education
(n=817)
Frail
(n=222)
Not frail
(n=596) All P Value
Frail
(n=217)
Not frail
(n=600) All
P
Value*
Mean (SD) age, years 79.9 ± 5.4 78.2 ± 5.1 78.7 ± 5.2 <0.001 80.4 ± 5.3 78.6 ± 5.1 79.1 ± 5.2 <0.001
Female sex 165 (74%) 382 (64%) 547 (67%) 0.006 169 (78%) 382 (64%) 551 (67%) <0.001
Mean (SD) 3MSE, score 90.8 ± 5.7 91.8 ± 5.4 91.5 ± 5.5 0.020 90.7 ± 5.5 92.0 ± 5.2 91.6 ± 5.3 0.003
Mean (SD) CES-D, score 12.4 ± 9.3 6.9 ± 6.5 8.3 ± 7.7 <0.001 12.4 ± 8.8 7.6 ± 7.2 8.8 ± 7.9 <0.001
Mean (SD) number of
chronic conditions
1.9 ± 1.2 1.7 ± 1.1 1.8 ± 1.1 0.028 2.1 ± 1.2 1.8 ± 1.1 1.8 ± 1.2 0.002
Mean (SD) SPPB, score 6.7 ± 1.8 7.7 ± 1.4 7.4 ± 1.6 <0.001 6.3 ± 1.7 7.7 ± 1.4 7.3 ± 1.6 <0.001
Mean (SD) number of Fried
frailty index criteria
3.3 ± 0.5 1.4 ± 0.7 1.9 ± 1.0 <0.001 3.2 ± 0.4 1.4 ± 0.7 1.9 ± 1.0 <0.001
Frail according to Fried index: 26.9 % (439/1635)
Frail according to SOF index: 19.6% (321/1635)
BASELINE CHARACTERISTICS OF PARTICIPANTS BY RANDOMIZATION GROUPS AND FRAILTY STATUS
* Frail vs not frail subjects within group of randomization
Physical activity
(n=818) Health education (n=817)
Fried frailty index
Baseline prevalence of frailty 222 (0.27) [0.24-0.30] 217 (0.27) [0.24-0.30]
Baseline prevalence of not frailty 596 (0.73) [0.70-0.76] 600 (0.73) [0.70-0.77]
Cumulative incidence Cumulative incidence
6 Month 54 (0.18) [0.13-0.23] 73 (0.24) [0.19-0.30]
12 Month
24 Month
109 (0.20) [0.16-0.23]
154 (0.15) [0.13-0.18]
125 (0.22) [0.19-0.26]
177 (0.18) [0.15-0.20]
SOF frailty index
Baseline prevalence of frailty 159 (0.19) [0.17-0.22] 162 (0.20) [0.17-0.23]
Baseline prevalence of not frailty 659 (0.81) [0.78-0.83] 655 (0.80) [0.77-0.83]
Cumulative incidence Cumulative incidence
6 Month 71 (0.22) [0.17-0.27] 102 (0.31) [0.25-0.37]
12 Month 127 (0.21) [0.17-0.24] 138 (0.23) [0.19-0.27]
24 Month 177 (0.16) [0.14-0.19] 195 (0.18) [0.15-0.20]
INCIDENCE OF FIRST INITIAL FRAILTY ACCORDING TO RANDOMIZATION GROUP AT EACH VISIT
Data are presented as n (count/person year) [95% CI for incidence]
GEE MODELS PREDICTING FRAILTY OVER 24 MONTHS ACCORDING TO RANDOMIZATION GROUP
Unadjusted odds
ratio (95% CI) P Value
Adjusted odds
ratio* (95% CI) P Value
Fried frailty index
Physical activity (n=818) 0.83 [0.69-0.99] 0.040 0.81 [0.68-0.98] 0.028
Health education (n=817)
(Reference)
SOF frailty index
Physical activity (n=818) 0.81 [0.67-0.98] 0.034 0.86 [0.71-1.04] 0.125
Health education (n=817)
(Reference)
* Baseline value of the outcome, gender and field center (both used to stratify randomization), age,
intervention, clinic visit, and intervention-by-visit interaction included in the models.
ESTIMATED EFFECTS OF THE INTERVENTION ON THE MEAN NUMBER OF FRIED FRAILTY CRITERIA
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2
Baseline Month 6 Month 12 Month 24
Mean
Nu
mb
er
of
Fra
ilty
Cri
teri
a Health education
Average effect: P<0.001
P<0.001 P<0.003 P<0.001
MAJOR MOBILITY DISABILITY AND PERSISTENT MAJOR MOBILITY DISABILITY OCCURRENCE
IN FRAIL PARTICIPANTS AT BASELINE
HR=0.69 [CI, 0.49-0.98]; P=0.04 HR=0.58 [CI, 0.39-0.91]; P=0.01
Major mobility disability* Persistent mobility disability
Overall, the interaction term between frailty and randomization arm was not significant for major mobility disability outcome (P=0.31).
Summary: Age-associated skeletal muscle
dysfunction (Sarcopenia) is a key biological mediator of the frailty syndrome.
24 months of a structured, moderate-intensity physical activity program significantly reduced the risk and severity of frailty.
Among frail individuals, the risk of major mobility disability was reduced by 31% with the physical activity intervention, while falls and fractures risks were not modified. These results stress the need to engage even the more frail individuals in such programs.
Function promoting anabolic therapies should be evaluated with respect to their efficacy in both non-frail and frail older adults.
Pathology: reduced muscle size, neural activation/recruitment, mitochondrial function, local
vascular change
(WHO: Body Function, Structure)
Impairment: muscle strength/power, aerobic/endurance capacity
Functional Limitation*:
gait speed, chair rise time
(WHO: Activity)
Disability*: role limitations
(WHO: Participation) *Nagi, 1965; Verbrugge & Jette, 1994
The Disablement Pathway*, Intrinsic Capacity, Frailty,
and Sarcopenia
Intrinsic Capacity
Functional Ability
PA HE PA HE PA HE PA HE PA HE PA HE PA HE
Baseline
Month 6
Month 12
Month 24
PA = Physical activity HE = Health education
Pre
va
len
ce
(%
)
Fried
Exhaustion SOF
Reduced
energy level
Fried / SOF
Weight loss SOF
Inability to
rise from a
chair 5 times
Fried
Sedentariness
Fried
Slow gait
speed
Fried
Poor muscle
strength
Average effect:
P<0.004
Average effect:
P<0.001
ESTIMATED EFFECTS OF THE INTERVENTION ON THE PREVALENCE OF EACH OF FRIED
AND SOF FRAILTY CRITERION
0
10
20
30
40
50
60
70
80
90
100